系统炎症微环境中HMGB1对骨髓间充质干细胞信号成骨分化的调控机制研究

Multiple injuries ususlly cause systematic aseptic inflammation due to soft tussue injury and multiple fractures.Systematic inflammation will delay fracture healing or cause fracture nonunion.However,the mechanism of systematic inflammation microenvironment affecting fracture healing is still unclear.HMGB1 is the key factor mediating systematic inflammation.Mesenchymal stem cells (MSC) are the main cells for osteogenesis.Our previous study found that HMGB1 had different effects on the osteogenesis of MSC in different ossification stages and the amounts of MSC expressed HMGB1 receptors were also different during different ossification stages.So we propose that the change of MSC expressed receptors for HMGB1 during different ossification stages results in the different effects of HMGB1 on osteogenesis.In order to proving our hypothesis,we will inspect the receptors of HMGB1 expression on MSC during ossification and find out the correlation between receptors expression,osteogenesis and secreted factors.We will assess the effects of HMGB1 on osteogenesis signal pathways changes and find out related mechanisms.Through fracture animal model with system inflammation, we will find out how HMGB1 in the system inflammation microenvironment influence fracture healing in tissue aspect.Our study will provde some experimental and theoretical proofs for the treatment and improvement the prognosis of patients with multiple injury and multiple fractures.

多发伤患者由于软组织和多发骨折引起机体无菌性系统炎症反应。系统炎症引起骨折愈合延迟或骨不连，但系统炎症微环境对骨折愈合影响的机制目前尚不清楚。HMGB1是系统炎症的关键介导因子,骨髓间充质干细胞(MSC)是成骨分化的主要细胞。前期研究发现HMGB1在成骨分化不同阶段具有不同的作用，而成骨分化不同阶段MSC表面HMGB1受体表达发生改变。因此，我们提出HMGB1对成骨分化的影响是通过MSC表面HMGB1受体在成骨分化的不同阶段表达发生改变而实现的假说。为此，通过检测MSC成骨分化不同阶段HMGB1受体的表达，研究受体表达变化与成骨分化、分泌相关因子之间的时效关系；检测HMGB1作用MSC后相关信号通路改变，探讨相关机制；通过系统炎症骨折动物模型，从组织学角度阐明系统炎症微环境对骨折愈合影响机制。本研究可以为临床中多发伤、多发骨折患者的治疗和改善预后提供一定的理论和实验依据。

多发伤患者由于软组织和多发骨折引起机体无菌性系统炎症反应。系统炎症引起骨折愈合延迟或骨不连，但系统炎症微环境对骨折愈合影响的机制目前尚不清楚。HMGB1是系统炎症的关键介导因子,骨髓间充质干细胞(MSC)是成骨分化的主要细胞。我们在前期研究的基础上，通过体外分子生物学研究以及抗体芯片等技术研究发现HMGB1可以促进MSC定向迁移和成骨分化。HMGB1的定向迁移主要是通过p38和Rap1信号途径。而HMGB1的促成骨机制主要是通过p38 MAPK途径和Ras/MAPK途径。我们在体外研究的基础上进一步通过体内研究证实HMGB1可以在体内促进骨折修复和愈合。本研究可以为临床中多发伤、多发骨折患者的治疗和改善预后提供一定的理论和实验依据。